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Among the 2446 patients who received tacrine in clinical trials,ALT levels greater than the upper limit of normal(ULN)occurred on at least one occasion in 1203 patients(49%),ALT levels greater than three times the ULN occurred in 621 patients(25%),and ALT levels greater than 20 times the ULN occurred in 40 patients(2%).The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men.The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days,and 90%of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment.Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged,127(88%)were able to resume long-term therapy with the drug.In all instances,discontinuing tacrine completely reversed elevations in ALT levels,and no deaths related to hepatotoxicity occurred.These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy. |
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